Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription regulator belonging to an intranuclear receptor family. This family is identified as a family of transcription regulators involved in regulating expression of a lipid metabolism-maintaining gene group. In mammalian animals, the presence of 3 subtypes, i.e. PPARα, PPARδ (PPARβ, NUC-1, FAAR) and PPARγ, is known, and PPARα is expressed mainly in the liver and PPARδ is universally expressed. For PPARγ, there are 2 isoforms, i.e. PPARγ1 and PPARγ2, and PPARγ1 is expressed not only in an adipose tissue but also in an immune organ, adrenal gland and small intestine. PPARγ2 is expressed specifically in an adipose tissue, and is a master regulator which regulates differentiation and maturation of an adipocyte (Teruo Kawada, “Igaku No Ayumi”, 184, 519-523, 1998).
As PPARγ ligands, synthetic compounds including thiazolidine derivatives such as troglitazone, pioglitazone and rosiglitazone are known. As PPARγ ligands, naturally occurring compounds including arachidonic acid metabolites such as 15-deoxy-Δ12,14-prostaglandin J2 and Δ12-prostaglandin J2, unsaturated fatty acids such as ω-3 multivalent unsaturated fatty acid, x-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and eicosanoids such as 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid are known (J. Auwerx, Diabetologia, 42, 1033-1049, 1999). Japanese Kokai Publication 2000-355538 discloses a C10-26 conjugated unsaturated fatty acid having a conjugated triene structure or a conjugated tetraene structure. For flavonoids, chrysin and apigenin as flavone derivatives and kaempferol as a flavonol derivative are reported to be PPARγ ligands (Y. C. Liang, et al., FEBS Letters, 496, 12-18, 2001). A flavonoid is a component contained widely in plants, and is known to have antioxidant properties. However, it is not known that a prenylflavonoid contained only in a specific plant is a PPARγ ligand.
The agonistic activity of a thiazolidine derivative as PPARγ ligand is correlated with its hypoglycemic action, thus the derivative has attracted attention for its relationship with an ameliorating action on insulin resistance and been developed as an insulin resistance ameliorator for type 2 diabetes mellitus (non-insulin dependent diabetes mellitus: NIDDM). That is, a thiazolidine derivative, which is a PPARγ ligand, activates PPARγ thereby increasing a normally functioning small adipocyte differentiated from a preadipocyte. Thereafter, a hypertrophic adipocyte, in which over-production and over-secretion of TNFα and a free fatty acid inducing insulin resistance, is reduced with apotosis. As a result, insulin resistance is ameliorated (A. Okuno, et al., Journal of Clinical Investigation, 101, 1354-1361, 1998). A PPARγ ligand ameliorates insulin resistance and is thus also effective in preventing and/or ameliorating the insulin resistance syndrome including not only type 2 diabetes mellitus but also hyperinsulinemia, dyslipidemia, obesity (in particular visceral fat obesity), hypertension and arteriosclerosis (R. A. DeFronzo & E. Ferrannini, Diabetes Care, 14, 173-194, 1991). Pathologic conditions in the same category as the insulin resistance syndrome include Syndrome X (G. M. Reaven, Diabetes, 37, 1595-1607, 1988), the deadly quartet (N. M. Kaplan, Archives of Internal Medicine, 149, 1514-1520, 1989) and the visceral fat syndrome (Y. Matsuzawa, Diabetes/Metabolism Reviews, 13, 3-13, 1997).
A PPARγ ligand is also effective in preventing and/or ameliorating inflammations and cancers because of its inhibition of inflammatory cytokine production (C. Jiang, et al., Nature, 391, 82-86, 1998) and its induction of apotosis thereby inhibiting growth of cancer cells (Y. Tsubouchi, et al., Biochemical and Biophysical Research Communications, 270, 400-405, 2000).